Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
  • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/13—Amines
  • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
  • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/16—Amides, e.g. hydroxamic acids
  • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
  • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
  • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
  • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/365—Lactones
  • A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
  • A61K31/52—Purines, e.g. adenine
  • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
  • A61K36/18—Magnoliophyta (angiosperms)
  • A61K36/185—Magnoliopsida (dicotyledons)
  • A61K36/25—Araliaceae (Ginseng family), e.g. ivy, aralia, schefflera or tetrapanax
  • A61K36/258—Panax (ginseng)
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2013—Organic compounds, e.g. phospholipids, fats
  • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
  • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
  • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
  • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer

Definitions

• the invention relates to the field of chewable tablets for oral delivery of active ingredients.
• the invention relates to multi-layered tablets suitable for high load delivery of active ingredients.
• multi-layered tablets may be difficult to produce with suitable results. Often, these tablets are friable and therefore less preferred in terms of disadvantages of storing and transporting the tablets.
• the compression process gives some limitations on the amount of actives to be incorporated in the layers of the tablets,
• a pre-compression step in the tableting procedure for a first layer of the tablets may give rise to problems with friability once a second layer is applied on top of the first layer.
• a high load of active ingredients may cause issues for the overall sensorial properties of multi-layered tablets. Both the nature of the active ingredients with respect to taste properties and pronounced bitterness for some active ingredients, and the high amount of actives relative to other ingredients in the multi-layered tablets, may be a challenge to formulation specialists.
• Sensorial properties in the present context include the overall mouthfeel of the multi-layered tablet when chewed and the resulting delivery of the active ingredients in the oral cavity. For instance, a pronounced powdery sense is often not convenient to the user and as a result may often provide inferior multi-layered tablets that are not used on a frequent basis.
• a multi-layered tablet is to be provided that may also help in obtaining improved sensorics properties.
• important sensorics properties include friability, texture, flavor perception, sweetness perception and off-notes associated with the actives. These properties are both relevant from a convenience perspective in chewable multi-layered tablets, but certainly also in order to support an appropriate delivery of actives from the multi-layered tablets and avoid adverse side effects of the actives.
• actives may tend to be associated with off-notes during administration due to the specific physiochemical properties of the compounds.
• the taste masking challenge is more profound when a higher release of the actives are delivered by such multi-layered tablets. If off-notes are the predominant sensation during administration, convenience may be affected and even more critically, the delivery of the actives may also be affected. Saliva production may be suppressed, and the delivery vehicle may not be handled correctly. Further, even when sensorial properties to some degree are complied with, there would usually also be a desire for relative fast delivery of active ingredients upon oral administration. Often, this desire of a relative fast release is counteracted by the desire for taste-masking of the active ingredients.
• chewable multi-layered tablet formulations may help in obtaining a release characteristic of actives that offers increased convenience and effectiveness.
• One of these release characteristics is increased generation of saliva upon chewing.
• Increased saliva generation and particularly an experience of increased saliva generation upon administration may have some pronounced benefits for delivery of actives.
• an oral chewable tablet comprising: dextrose in an amount from 50 to 95% by weight of the tablet; and one or more active ingredients in an amount from 0.1 to 50% by weight of the tablet, wherein the oral chewable tablet comprises: at least two compressed layers containing said dextrose and the one or more active ingredients, the first of the compressed layers being cohered to and adjacent to the second layer.
• the aim of the oral chewable multi-layered tablets according to the invention is the combination of a relatively high amount of dextrose and one or more active ingredients in a configuration that at the same time allows for more flexibility than a conventional oral chewable one-layered tablet.
• One advantage of the invention is a surprisingly strong saliva generation compared to conventional chewable tablets and lozenges. Increased generation of saliva may have a huge impact on the delivery of the one or more active ingredients. Specifically, when increased generation of saliva is coordinated with release of the one or more active ingredients from the multi-layered tablet, relatively quick delivery is obtained. Hence, a synergy between the effect of the one or more active ingredients and increased saliva generation may be seen according to the invention.
• One unexpected advantage over the prior art is that the saliva generation is surprisingly sustained even after a user has swallowed the bulk-portion of the dextrose. This sustaining of the salivation generation may be advantageous in relation to many applications of a chewable multi-layered tablet ranging from mouthfeel, taste, flavor perception, etc.
• the present invention may offer an improved release profile of the one or more active ingredients compared to conventional chewable one-layered tablets.
• the specific tablet formulation platform of the present invention may serve to provide improved release characteristics of the one or more active ingredients compared to conventional chewable one-layered tablet formulation platforms applied in combination with one or more active ingredients.
• a very important aspect of the present invention is the provision of beneficial sensorial properties.
• important sensorial properties include mouthfeel, ease of chewing/melting into liquid, friability (mechanical robustness), texture, flavor perception, sweetness perception and off-notes associated with the one or more active ingredients.
• the present inventor has shown very surprising results with the specific combination of features of the present invention in terms of these sensorial properties. It was an unexpected result that the invention could both contribute to an improved release profile, such as rapid release of the one or more active ingredients, and at the same time provide very beneficial sensorics properties which in terms may also support an appropriate delivery of the one or more active ingredients from the chewable multilayered tablet.
• the mouthfeel of the oral multi-layered tablet during use is critical for the release of the one or more active ingredients and the experience as well as convenience during use.
• the mouthfeel was improved which was not expected by the inventor of the present invention.
• a “chewable tablet” is intended to mean an oral tablet that is chewed upon oral administration, having characteristics allowing convenient chewing without adverse side effects associated with the texture of the oral tablet.
• Providing a layered tablet structure according to the invention may solve various problems of the prior art and aims at establishing a platform that combines beneficial delivery properties of actives combined with advantageous sensorial properties.
• a ‘layer’ is to be understood as a matrix resulting from pressing one portion of particles according to the invention.
• This portion may comprise one or more populations of particles.
• this portion when a portion of particles according to the invention is applied in the tableting apparatus, and this portion is pressed into a coherent tablet, this would correspond to one ‘layer’ or a ‘first layer’.
• such layer may be pressed in two steps with varying pressure.
• a pre-compression pressure is applied to the first portion being pressed. This pressure will typically be lower than for a ‘second layer’. Pre-compression serves various purposes, such as aligning the first portion with a sharp visual line in the periphery of the multi-layered tablet. Another purpose of substantial character is that it serves to provide a solid support for a “second layer”, thereby establishing bonds between the particles of the material.
• this portion may comprise one or more populations of particles.
• the second layer may also be applied in the tableting apparatus first and the first layer may be applied in the tableting apparatus in a second step.
• the individual layers of the tableted composition would have a sharp line between the layers when the layers are pressed in two or more subsequent steps. This is seen from a side view of the tablet as distinct layers on top of each other.
• two or more portions are applied in subsequent steps to the tableting apparatus and pressed in one sequence. In this case there will not be a sharp line between the layers from a side view, but this would still be considered a layered tablet according to the invention, although the line between the layers would be irregular. Accordingly, in some embodiments, it is not required that layers are processed in separate tableting steps, preferably with a pre-compression step.
• the layers have a tablet-slice appearance.
• the tablet consists of two layers.
• the weight ratio of the first layer relative to the second layer is from 1 : 10 to 10: 1.
• controlled release of the one or more active ingredients may be facilitated. Also, sensorial properties of the tablet may be improved.
• the weight ratio of the first layer relative to the second layer is from 1 :5 to 5: 1. In some embodiments of the invention, the weight ratio of the first layer relative to the second layer is from 3: 10 to 10:3. In some embodiments of the invention, the weight ratio of the first layer relative to the second layer is from 1 :2 to 2: 1.
• tablet consists of three layers where the first layer is the middle layer, and the second layer is cohered to and adjacent to one side of the first layer, and a third layer is cohered to and adjacent to the opposite side of the first layer.
• ‘cohered to and adjacent to’ is intended to mean that two outer layers are located on and attached to one top side and one bottom side of a middle layer. Seen from a side view, the layers have a tablet-slice appearance.
• the weight ratio of the first layer relative to the second layer relative to the third layer is from 1 :5:5 to 10: 1 : 1. In some embodiments of the invention, the weight ratio of the first layer relative to the second layer relative to the third layer is from 1:3:3 to 3: 1 :1.
• controlled release of the one or more cannabinoids may be facilitated. Also, sensorial properties of the tablet may be improved.
• the weight ratio of the first layer relative to the second layer relative to the third layer is from 1 :4:4 to 8: 1 : 1. In one embodiment of the invention, the weight ratio of the first layer relative to the second layer relative to the third layer is from 1 :4:4 to 6: 1 : 1. In one embodiment of the invention, the weight ratio of the first layer relative to the second layer relative to the third layer is from 1 :4:4 to 4: 1 : 1.
• tableting implies that the particles are reduced in volume as a result of pressure applied in the tableting apparatus.
• the particles may be free flowing before tableting, once the particles have been pressed, the volume of the particles is reduced, and the particles are cohered together into a continuous matrix, which in the present context is denoted a ‘layer’.
• the individual particles are not merged after tableting but remain individual ‘discrete’ areas after tableting, constituting the individual particles. Some integration of the particles may be present but generally the particles remains discrete areas of the tablet.
• the oral chewable tablet is made by direct compression in a tableting machine.
• the first layer is a pre-compressed layer and the second layer is compressed on top of the first layer.
• the first layer is pre-compressed by direct compression in a tableting machine and the second layer is compressed on top of the first layer in the tableting machine.
• the first layer is pre-compressed by direct compression in a tableting machine and the second layer is compressed on top of the first layer in the tableting machine with a higher pressure.
• the second layer is compressed on top of the first layer with a pressure that is operable to avoid breaking of the tablet during compression.
• breaking of the tablet during compression is intended to mean the tablet is subject to a fracture during compression in a more or less pronounced degree.
• the second layer is compressed on top of the first layer with a pressure that is operable to avoid capping of the tablet.
• Tablet capping is the most common defect. It is when the shaped dome of the tablet fractures away from the body of the tablet. When compressing a tablet, the air is pushed out from between the granules, which allows them to be locked together. If the particles are too dry, over-lubricated or highly elastic, they do not bond together sufficiently. The stress of ejection can open up small microcracks within the compact, which expand and lead to the cap being sheared apart from the body.
• the second layer is compressed on top of the first layer with a pressure that is operable to avoid de-lamination of the tablet. Lamination of tablets may occur when the product separates into horizontal layers. Lamination is very similar to capping, but occurs in the main body of the tablet, not at the top, and it can occur immediately after compression or during the storage period.
• dextrose is present in an amount from 55 to 95% by weight of the tablet. In some embodiments of the invention, dextrose is present in an amount from 60 to 95% by weight of the tablet. In some embodiments of the invention, dextrose is present in an amount from 65 to 95% by weight of the tablet. In some embodiments of the invention, dextrose is present in an amount from 70 to 95% by weight of the tablet. In some embodiments of the invention, dextrose is present in an amount from 70 to 90% by weight of the tablet.
• the oral chewable tablet is consisting essentially of dextrose, one or more active ingredients, one or more binders added separately in the formulation and being separate from any binder being integrated in other ingredients in the tablet, and auxiliary ingredients present up to about 5% by weight of the tablet.
• the oral chewable tablet is consisting essentially of dextrose, one or more active ingredients, and auxiliary ingredients present up to about 5% by weight of the tablet.
• Flavors, high intensity sweeteners and glidant are examples of auxiliary ingredients that may be added in low amounts according to the invention without compromising the platform according to the invention.
• a major part of the chewable tablets is composed of dextrose and the one or more active ingredients according to the invention.
• the overall system of the chewable tablet is controlled by these ingredients, including the special improved sensorial benefits of the invention, such as an improved mouth-feel, as well as saliva generation, and as well as friability properties.
• the oral chewable tablet is consisting essentially of dextrose, one or more active ingredients and one or more binders.
• the oral chewable tablet does not comprise sugar alcohol. It is contemplated that sugar alcohols in some embodiments are detrimental to the platform properties according to the invention, including sensorial properties, such as mouth-feel. In some embodiments, however, low amounts of sugar alcohol may be added, such as low amount of mannitol, such as less than 5% by weight.
• the oral chewable tablet does not comprise gum base.
• the presence of gum base may impact the sensorial properties of the tablet as well as release of active ingredients.
• the dextrose is based on controlled enzymatic hydrolysis of starch.
• the dextrose comprises anhydrous dextrose. In some embodiments of the invention, the dextrose comprises hydrated dextrose. In some embodiments of the invention, the dextrose comprises dextrose monohydrate. In some embodiments of the invention, the dextrose comprises at least 90% dextrose equivalents calculated on a dry basis. In some embodiments of the invention, the dextrose comprises at least 93% dextrose equivalents calculated on a dry basis. In some embodiments of the invention, the dextrose comprises at least 95% dextrose equivalents calculated on a dry basis. In some embodiments of the invention, the dextrose comprises at least 98% dextrose equivalents calculated on a dry basis.
• the dextrose comprises a purified mixture of saccharides. In some embodiments of the invention, the dextrose comprises oligomeric saccharides. In some embodiments of the invention, the dextrose comprises 93 to 97% dextrose equivalents calculated on a dry basis. In some embodiments of the invention, the dextrose comprises microcrystalline dextrose. In some embodiments of the invention, the dextrose comprises dextrate.
• the dextrose does not comprise maltodextrin.
• the dextrose comprises 100% dextrose equivalents calculated on a dry basis.
• Dextrose in a pure version comprises 100% dextrose equivalents calculated on a dry basis and is presently preferred as the dextrose applied in the present invention.
• dextrose is pure and is based on 100% conversion of starch to dextrose.
• the dextrose is directly compressible (DC).
• the dextrose is a powder.
• the oral chewable tablet comprises at least one grade of dextrose. In some embodiments of the invention, the oral chewable tablet comprises at least two grades of dextrose. In some embodiments of the invention, the oral chewable tablet comprises at least three grades of dextrose.
• the oral chewable tablet comprises different grades of dextrose in different layers of the tablet. In some embodiments of the invention, the oral chewable tablet comprises at least one grade of dextrose containing a binder. In some embodiments of the invention, the oral chewable tablet comprises at least one grade of dextrose containing maltodextrin. In some embodiments of the invention, the oral chewable tablet comprises at least one grade of dextrose being granules comprising dextrose and one or more binders. In some embodiments of the invention, the oral chewable tablet comprises at least one grade of dextrose without one or more binders being integrated in the grade.
• the dextrose comprises at least 30% by weight of particles in the range of 180 to 500 microns. In some embodiments of the invention, the dextrose comprises at least 50% by weight of particles in the range of 180 to 500 microns. In some embodiments of the invention, the dextrose comprises at least 30% by weight of particles in the range of 250 to 500 microns. In some embodiments of the invention, the dextrose comprises at least 50% by weight of particles above 250 microns. In some embodiments of the invention, the dextrose comprises at least 10% by weight of particles above 500 microns
• the dextrose comprises at most 35% by weight of particles below 100 microns. In some embodiments of the invention, the dextrose comprises at most 10% by weight of particles above 500 microns.
• One presently preferred grade of dextrose comprises C*DexTM 02001 provided by Cargill. This grade is also referred to as a fine grade of dextrose due to the particle size distribution with a relatively high portion of particles with a small particles size.
• Another grade of dextrose comprises Cerelose® dextrose 020010 provided by Ingredion which has a particle size distribution similar to C*DexTM 02001.
• the dextrose comprises at most 5% by weight of particles below 100 microns. In some embodiments of the invention, the dextrose comprises at most 20% by weight of particles below 250 microns.
• One grade of dextrose comprises C*DexTM 02032 provided by Cargill.
• Another grade of dextrose comprises C*DexTM 02030 provided by Cargill. This grade is also referred to as a coarse grade of dextrose due to the particle size distribution with a relatively higher portion of particles with a larger size.
• the dextrose comprises at most 25% by weight of particles below 149 microns.
• the dextrose comprises at most 35% by weight of particles below 177 microns. In some embodiments of the invention, the dextrose comprises at least 5% by weight of particles above 1190 microns.
• One grade of dextrose comprises Royal-T® provided by Ingredion. This grade contain maltodextrin within the particles, i.e., the particles have been subject to granulation with maltodextrin.
• the grade of dextrose may impact the compression configuration. For instance, by providing a coarse grade of dextrose certain challenges of capping or de-lamination may be avoided upon compression of the multi-layered tablets according to the invention. Accordingly, in some embodiments it is preferred with a more course grade of dextrose, or a grade with an integrated content of maltodextrin.
• the oral chewable tablet comprises one or more binders added separately in the formulation and being separate from any binder being integrated in other ingredients in the tablet.
• the one or more binders is present in an amount of 0.4 to 5% by weight of the tablet. In some embodiments of the invention, the one or more binders is present in an amount of 0.5 to 4% by weight of the tablet. In some embodiments of the invention, the one or more binders is present in an amount of 0.7 to 3% by weight of the tablet. In some embodiments of the invention, the one or more binders is present in an amount of 0.7 to 2% by weight of the tablet. In some embodiments of the invention, the one or more binders is present in an amount of 0.7 to 1.3% by weight of the tablet. In some embodiments of the invention, the one or more binders is present in an amount of 2 to 15% by weight of the tablet. In some embodiments of the invention, the one or more binders is present in an amount of 3 to 10% by weight of the tablet.
• the one or more binders is present in an amount of 4 to 6% by weight of the tablet. In some embodiments of the invention, the one or more binders is present in an amount of 2 to 7% by weight of the tablet. In some embodiments of the invention, the one or more binders is present in an amount of 2 to 5% by weight of the tablet. In some embodiments of the invention, the one or more binders is present in an amount of 3 to 7% by weight of the tablet. In some embodiments of the invention, the one or more binders is present in an amount of 3 to 6% by weight of the tablet. In some embodiments of the invention, the one or more binders is present in an amount of 3 to 5% by weight of the tablet.
• the one or more binders is selected from the group consisting of hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), maltodextrin, and combinations thereof.
• the one or more binders is selected from the group consisting of hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), and combinations thereof.
• the one or more binders comprise hydroxypropyl cellulose (HPC). In some embodiments of the invention, the one or more binders is hydroxypropyl cellulose (HPC). HPC may be applied as a particular attractive binder. Thus, this binder, when used with dextrose, exhibits an advantageous sensory experience when compared to other well-known binders.
• the one or more binders comprise hydroxypropyl methylcellulose (HPMC). In some embodiments of the invention, the one or more binders is hydroxypropyl methylcellulose (HPMC). HPMC may be applied as a particular attractive binder. Thus, this binder, when used with dextrose, exhibits an advantageous sensory experience when compared to other well-known binders.
• the one or more binders comprises maltodextrin.
• the one or more binders does not comprise microcrystalline cellulose (MCC). It is contemplated that MCC is poor in relation to sensorial properties according to the invention.
• the one or more binders does not comprise silica, cellulose, silicified microcrystalline cellulose, clay, talc, starch, pregelatinized starch, calcium carbonate, dicalcium phosphate, magnesium carbonate, magnesium- alumino-metasilicates, hyper porous silica and mixtures thereof.
• the oral chewable tablet does not comprise one or more binders added separately in the formulation and being separate from any binder being integrated in other ingredients in the tablet.
• the oral chewable tablet comprises one or more binders integrated in other ingredients in the tablet, such as one or more binders present in granules comprising dextrose.
• the one or more active ingredients is present in an amount of 5 to 50% by weight of the tablet.
• the one or more active ingredients is present in an amount of 10 to 50% by weight of the tablet.
• the one or more active ingredients is present in an amount of 20 to 50% by weight of the tablet. In some embodiments of the invention, the one or more active ingredients is present in an amount of 30 to 50% by weight of the tablet.
• the one or more active ingredients is present in an amount of 5 to 40% by weight of the tablet.
• the one or more active ingredients is present in an amount of 5 to 30% by weight of the tablet.
• the one or more active ingredients is present in an amount of 10 to 30% by weight of the tablet.
• the one or more active ingredients comprise a non-directly compressible (non-DC) active ingredient.
• the one or more active ingredients is located in the first layer of the tablet. In some embodiments of the invention, the one or more active ingredients is located in the second layer of the tablet. In some embodiments of the invention, the one or more active ingredients is both located in the first and second layer of the tablet. In some embodiments of the invention, one active ingredient is located in the first and another active ingredient is located in the second layer of the tablet. In some embodiments of the invention, one of the layers of the tablet does not comprise the one or more active ingredients.
• the one or more active ingredients comprise a non-directly compressible (non-DC) active ingredient. In some embodiments of the invention, the one or more active ingredients comprise a non-directly compressible (non-DC) active ingredient in an amount of 5 to 50% by weight of the tablet. In some embodiments of the invention, the one or more active ingredients comprise a non- directly compressible (non-DC) active ingredient in an amount of 10 to 50% by weight of the tablet. In some embodiments of the invention, the one or more active ingredients comprise a non-directly compressible (non-DC) active ingredient in an amount of 20 to 50% by weight of the tablet. In some embodiments of the invention, the one or more active ingredients comprise a non-directly compressible (non-DC) active ingredient in an amount of 30 to 50% by weight of the tablet.
• the one or more active ingredients comprise a directly compressible (DC) active ingredient.
• DC directly compressible
• the one or more active ingredients comprise an immune supporting active ingredient.
• the one or more active ingredients comprise a mixture of immune supporting active ingredients.
• the one or more active ingredients comprise an energy stimulating active ingredient
• the one or more active ingredients comprise a mixture of vitamins, minerals, and herbals.
• the one or more active ingredients comprise Vitamin C. In some embodiments of the invention, the one or more active ingredients comprise melatonin. In some embodiments of the invention, the one or more active ingredients comprise theanine. In some embodiments of the invention, the one or more active ingredients comprise calcium carbonate. In some embodiments of the invention, the one or more active ingredients comprise caffeine.
• the one or more active ingredients comprise multivitamin. In some embodiments of the invention, the one or more active ingredients comprise Zn-oxide. In some embodiments of the invention, the one or more active ingredients comprise Zn-citrate. In some embodiments of the invention, the one or more active ingredients comprise Zn-gluconate. In some embodiments of the invention, the one or more active ingredients comprise Vitamin D.
• the one or more active ingredients comprise acetaminophen. In some embodiments of the invention, the one or more active ingredients comprise phenylephrine. In some embodiments of the invention, the one or more active ingredients comprise dextromethorphan. In some embodiments of the invention, the one or more active ingredients comprise guaifenesin. In some embodiments of the invention, the one or more active ingredients comprise a combination of acetaminophen, phenylephrine, dextromethorphan, and guaifenesin.
• the one or more active ingredients comprise diphenhydramine. In some embodiments of the invention, the one or more active ingredients comprise loratadine. In some embodiments of the invention, the one or more active ingredients comprise nicotine.
• the active ingredient is selected from acetylcysteine, ambroxol, amylmetacresol, benzocaine, bisacodyl, bismuth subsalicylate, bromhexine, cetirizine, , dextromethorphan hydrobromide, 2,4- di chlorobenzyl alcohol, doxylamine succinate, , flurbiprofen, glycerin, hexylresorcinol, lidocaine, menthol, myrrh, paracetamol, pectin, peppermint oil, phenol, phenylephrine hydrochloride, povidone-iodine, pseudoephedrine, ranitidine, simethicone, sodium docusate, spearmint, zinc, or any combination thereof.
• active ingredients are active ingredients that may be delivered to the throat.
• the tablet may comprise further active ingredient, e.g. a combination of two or more active ingredients from the above list, or as a combination of an active ingredient from the above list and another active ingredient.
• the active ingredient is an analgesic.
• analgesics include e.g. ibuprofen, paracetamol (acetaminophen), ketoprofen, aspirin (acetylsalicylic acid), and naproxen.
• the active ingredient is an anesthetic.
• the active ingredient is an anti-inflammation agent.
• the active ingredient is a disinfectant.
• the active ingredient is a cough suppressant.
• cough suppressants include e.g. dextromethorphan.
• the active ingredient is an expectorant, such as guaifenesin.
• the active ingredient is a local anesthetic.
• local anesthetics include e.g. ambroxol, benzocaine and hexylresorcinol.
• the active ingredient is a member of the morphinan class.
• members of the morphinan class include e.g. dextromethorphan.
• the active ingredient is a non-steroidal antiinflammatory drug (NSAID).
• NSAIDs non-steroidal anti-inflammatory drugs
• flurbiprofen examples include e.g. flurbiprofen.
• the active ingredient is an anti-inflammation agent. In an embodiment of the invention the active ingredient is a disinfectant.
• the active ingredient is a cough and cold agent.
• the tablet comprises cough and cold agents including acetaminophen, dextromethorphan hydrobromide, guaifenesin and phenylephrine hydrochloride.
• the tablet comprises cough and cold agents including acetaminophen, dextromethorphan hydrobromide and phenylephrine hydrochloride.
• the active ingredient is an antihistamine.
• the active ingredient is an antibiotic.
• antibiotics include e.g. ampicillin, erythromycin, tetracycline, clarithromycin, penicillin, and metronidazole.
• the active ingredient is an enzyme.
• One advantage of enzymes may be that digestion may be accelerated and/or that intestinal balance is restored or improved.
• the active ingredient is an opioid.
• the tablet is a medical device for alleviating or treating dysphagia by inducing saliva generation.
• the active ingredient is cetirizine. In an embodiment of the invention the active ingredient is bromhexine. In an embodiment of the invention the active ingredient is amylmetacresol. In an embodiment of the invention the active ingredient is paracetamol. In an embodiment of the invention active ingredient is acetaminophen. In an embodiment of the invention the active ingredient is dextromethorphan HBr. In an embodiment of the invention the active ingredient is guaifenesin. In an embodiment of the invention the active ingredient is phenylephrine HC1. In an embodiment of the invention the active ingredient is penicillin.
• the tablet further comprising a water-soluble fiber, such as inulin.
• the active ingredient comprises zinc gluconate and ascorbic acid. In an embodiment of the invention, the active ingredient comprises zinc.
• the tablet further comprising a plant extract, such as red clover or willow extract.
• the tablet further comprising a plant extract, such as Echinacea, Camille or Lavender.
• the plat extract is combined in the tablet with zinc gluconate and ascorbic acid.
• the oral tablet is essentially consisting of ingredients that are present in nature.
• the oral tablet comprises a natural high intensity sweetener, such as stevioside.
• the one or more active ingredients is selected from alginate, atenolol, aspirin (acetylsalicylic acid), ampicillin, aminosalicylates, anhydrous citric acid, aspirin, bisacodyl, bismuth subsalicylate, bupropion, caffeine, calcium, calcium carbonate, cetirizine, cimetidine, cisapride, clarithromycin, desloratadine, dexlansoprazole, diphenhydramine HC1, diphenhydramine citrate, dimenhydrinate, docusate erythromycin, dopamine, esomeprazole, famotidine, fexofenadine HC1, guaifenesin, hydrotalcite, ibuprofen, ketoprofen, lactase enzyme, lansoprazole, loratadine, lorcaserin, loperamide, loperamide HC1, magnesium, magnesium carbonate, magnesium hydrox
• the active ingredient comprises vitamin B. In some embodiments of the invention, the active ingredient comprises vitamin B3. In some embodiments of the invention, the active ingredient comprises vitamin B6. In some embodiments of the invention, the active ingredient comprises vitamin B 12.
• active ingredients are active ingredients that may be delivered to the gastrointestinal tract.
• the may comprise further active ingredient, e.g. a combination of two or more active ingredients from the above list, or as a combination of an active ingredient from the above list and another active ingredient.
• Further ingredients include herbals, such as Ashwagandha, ginseng, elderberry, Boswellia, green tea, green coffee bean extract, coffee fruit extract, willow bark, Ivy leaf, rose hip, chamonile, forsythia fruit extract, lemon balm, passionflower extract, zembrin, and root of marshmallow.
• the active ingredient comprises ginseng.
• the active ingredient is an analgesic.
• analgesics include e.g. ibuprofen, paracetamol (acetaminophen), ketoprofen, aspirin (acetylsalicylic acid), and naproxen.
• the active ingredient is an anesthetic.
• the active ingredient is an antiinflammation agent.
• the active ingredient is a disinfectant.
• the active ingredient is an antibiotic. Examples of antibiotics include e.g. ampicillin, erythromycin, tetracycline, clarithromycin, penicillin, and metronidazole.
• the active ingredient is selected from vitamins, minerals, and supplements (VMS).
• vitamins, minerals, and supplements include e.g. vitamin A, vitamin B, vitamin B 12, vitamin C, vitamin D, vitamin E, vitamin K.
• the tablet comprises a combination of caffeine, L-theanine, vitamin B3, vitamin B6, and vitamin B12. In some embodiments of the invention, the tablet comprises a combination of caffeine, and vitamin B6. In some embodiments of the invention, the tablet comprises a combination of ginseng, and vitamin B 12. In some embodiments of the invention, the tablet comprises a combination of melatonin, vitamin C, and zinc. In some embodiments of the invention, the tablet comprises a combination of L-theanine, and GABA. In some embodiments of the invention, the tablet comprises a combination of L-theanine, and bacopa.
• the active ingredient is a hormone.
• the active ingredient is melatonin.
• hormones include e.g. progesterone, testosterone, and melatonin.
• the active ingredient is a steroid.
• steroids include e.g. prednisolone and prednisone.
• the active ingredient is a proton pump inhibitor. Examples of proton pump inhibitors include e.g. rabeprazole, pantoprazole, esomeprazole, dexlansoprazole, lansoprazole, and omeprazole.
• the active ingredient is an antihistamine.
• antihistamines examples include e.g. cimetidine, ranitidine, famotidine, nizatidine, and desloratadine.
• Antihistamines are drugs to treat allergic rhinitis and other allergies. Antihistamines can give release to a person with nasal congestion, sneezing or hives caused by e.g. pollen, dust mites or animal allergy.
• the active ingredient is a triptan.
• triptans include e.g. sumatriptan.
• the active ingredient is a xerostomia mitigation agent, such as a xerostomia mitigation agent for cancer patients.
• the active ingredient is a migraine treatment agent.
• the active ingredient is an enzyme.
• the active ingredient is a probiotic ingredient. In an advantageous embodiment of the invention the active ingredient is a prebiotic ingredient.
• the active ingredient is a gastrointestinal medication.
• a gastrointestinal medication is understood as an active ingredient acting in the gastrointestinal tract.
• the active ingredient is an opioid. In an advantageous embodiment of the invention the active ingredient is an allergy medication. In an advantageous embodiment of the invention the active ingredient is loratadine. In an advantageous embodiment of the invention the active ingredient is diphenhydramine. In an advantageous embodiment of the invention the tablet is a medical device for alleviating or treating dysphagia by inducing saliva generation.
• the active ingredient is ampicillin. In an advantageous embodiment of the invention the active ingredient is ibuprofen.
• the active ingredient is ondansetron. In an advantageous embodiment of the invention the active ingredient is paracetamol (acetaminophen). In an advantageous embodiment of the invention the active ingredient is acetylsalicylic acid. In an advantageous embodiment of the invention the active ingredient is simethicone. In an advantageous embodiment of the invention the active ingredient is sodium docusate.
• the one or more active ingredients comprise an active pharmaceutical ingredient.
• friability of the tablet is less than 3%, such as less than 2%, such as less than 1.5%, wherein friability is measured according to European Pharmacopoeia 9.1, test method 2.9.7. by using a pharmaceutical friabilitytester PTF 10E from Pharma Test.
• the tablet generates more than 1.5 mL saliva within 30 seconds from onset of mastication. In some embodiments of the invention, the tablet generates more than 1.5 mL saliva within a period from 30 to 90 seconds from onset of mastication. In some embodiments of the invention, the tablet generates more than 1.5 mL saliva within a period from 90 to 180 seconds from onset of mastication. In some embodiments of the invention, the tablet generates more than 1.5 mL saliva within a period from 180 to 300 seconds from onset of mastication. In some embodiments of the invention, the oral chewable tablet further comprises a saliva production inhibiting agent for controlling saliva production.
• the oral chewable tablet is designed to release the active ingredient in the oral cavity and designed to deliver a part of the active ingredient to the throat as part of saliva generated upon mastication of the tablet. In some embodiments of the invention, the oral chewable tablet is designed to release the active ingredient in the oral cavity and designed to deliver a part of the active ingredient to the gastrointestinal tract as part of saliva generated upon mastication of the tablet. In some embodiments of the invention, oral chewable tablet comprises means for accelerated release of the one or more active ingredient.
• the oral chewable tablet comprises one or more disintegrants operable to disintegrate the tablet within a period of 2 minutes or less in contact with oral saliva.
• disintegrated or “disintegrate” is intended to mean that the tablet is no longer to be considered a tablet but the tablet has been reduced and/or dispersed in saliva.
• disintegrants greatly facilitate disintegration of the tablet according to the invention.
• disintegrants have previously been used in tablet formulation science, the particular combination of disintegrants with dextrose according to the application would have been seen as problematic in view of the specific properties of dextrose.
• Various problems were suspected by the inventors of the present application, such as sensorial drawbacks and concentration issues with a high load of the active ingredients.
• the oral chewable tablet comprises one or more disintegrants selected from the group consisting of sodium croscarmellose, crospovidone, sodium starch glycolate, and combinations thereof.
• the one or more disintegrants comprises crosslinked polyvinylpyrrolidone. In an embodiment of the invention, the one or more disintegrants comprises crosslinked polyvinylpyrrolidone and wherein at least 50% by weight of the cross-linked polyvinylpyrrolidone has a particle size below 50 micrometers.
• the one or more disintegrants comprises crosslinked polyvinylpyrrolidone and wherein at least 25% by weight of the cross-linked polyvinylpyrrolidone has a particle size below 15 micrometers.
• the first layer is compressed under a compression pressure of 1 to 5 kN. In some embodiments of the invention, the second layer is compressed under a compression pressure of 6 to 40 kN. In some embodiments of the invention, the second layer is compressed under a compression pressure of 10 to 30 kN.
• the oral chewable tablet in contact with saliva has a disintegration profile that varies less than 10% under a compression pressure of 10 to 30 kN.
• the unit weight of the tablet is from about 100 mg to about 2000 mg. In some embodiments of the invention, the unit weight of the tablet is from about 100 mg to about 1800 mg. In some embodiments of the invention, the unit weight of the tablet is from about 500 mg to about 1600 mg. In some embodiments of the invention, the unit weight of the tablet is from about 600 mg to about 1500 mg.
• the one or more active ingredients are present in an amount of 1 to 1000 mg. In some embodiments of the invention, wherein the one or more active ingredients are present in an amount of 1 to 800 mg. In some embodiments of the invention, the one or more active ingredients are present in an amount of 1 to 600 mg. In some embodiments of the invention, the one or more active ingredients are present in an amount of 50 to 250 mg. In some embodiments of the invention, the one or more active ingredients are present in an amount of 100 to 250 mg.
• the one or more active ingredients are present in an amount of 1 to 50 mg. In some embodiments of the invention, the one or more active ingredients are present in an amount of 1 to 40 mg. In some embodiments of the invention, the one or more active ingredients are present in an amount of 1 to 30 mg. In some embodiments of the invention, the one or more active ingredients are present in an amount of 1 to 20 mg. In some embodiments of the invention, the one or more active ingredients are present in an amount of 1 to 10 mg. In some embodiments of the invention, the one or more active ingredients are present in an amount of 1 to 5 mg. In some embodiments of the invention, the one or more active ingredients are present in an amount of 1 to 4 mg.
• the oral chewable tablet provides an improved mouthfeel compared to an oral chewable tablet comprising less than 50% by weight of dextrose.
• the oral chewable tablet provides an improved melting sensation compared to an oral chewable tablet comprising less than 50% by weight of dextrose.
• the oral chewable tablet provides an improved liquid sensation compared to an oral chewable tablet comprising less than 50% by weight of dextrose.
• the oral chewable tablet provides a less stickiness sensation compared to an oral chewable tablet comprising less than 50% by weight of dextrose. In some embodiments of the invention, the oral chewable tablet provides a less bitterness sensation from the one or more active ingredients compared to an oral chewable tablet comprising less than 50% by weight of dextrose.
• the oral chewable tablet provides improved taste masking compared to an oral chewable tablet comprising less than 50% by weight of dextrose.
• the oral chewable tablet provides an improved melting sensation compared to an oral chewable tablet comprising one or more separate binders.
• the oral chewable tablet is designed to turn into liquid within 60 seconds of mastication.
• the oral chewable tablet is designed to turn into liquid within 30 seconds of mastication.
• the oral chewable tablet is designed to turn into liquid within 15 seconds of mastication.
• the dextrose is evenly distributed in the tablet or at least one module of the tablet.
• One advantage of the above embodiment may be that the even distribution of the dextrose promotes an effective disintegration of the module upon mastication, e.g., due to lower mechanical strength contribution from the dextrose, thereby facilitating effective contacting of the resulting mastication fragments formed by the mastication with saliva, again increasing dissolving of the tablet. Also, the even distribution of the dextrose promotes a high number of mastication fragments with dextrose, which again effectively promotes salivation.
• the oral chewable tablet comprises a further tablet module with a different disintegration time.
• the resistance to crunching of the tablet is greater than 60N, such as greater than 70N, such as greater than 80N, such as greater than 90N, such as greater than 100 N, such as greater than 110, such as greater than 13 ON such as greater than 150N, wherein the resistance to crunching of the tablet is less than 300N, such as less than 250N, such as less than 200N, wherein the resistance to crunching is determined according to European Pharmacopoeia 9.1, test method 2.9.8. by using a pharmaceutical resistance to crunching tester model Pharma Test type PTB 311.
• High intensity artificial sweetening agents can also be used alone or in combination with the above dextrose.
• Preferred high intensity sweeteners include, but are not limited to sucralose, aspartame, salts of acesulfame, alitame, saccharin and its salts, cyclamic acid and its salts, glycyrrhizin, dihydrochalcones, thaumatin, monellin, stevioside (natural intensity sweetener) and the like, alone or in combination.
• Encapsulation of sweetening agents can also be provided using another tablet component such as a resinous compound.
• Usage level of the artificial sweetener will vary considerably and will depend on factors such as potency of the sweetener, rate of release, desired sweetness of the product, level and type of flavor used and cost considerations.
• the active level of artificial sweetener may vary from about 0.001 to about 3% by weight (preferably from about 0.02 to about 3% by weight).
• the usage level of the encapsulated sweetener will be proportionately higher.
• Combinations of sugar and/or non-sugar sweeteners may be used in the formulation.
• the tablet comprises flavor.
• the amount of flavor may e.g., be from 0.1 to about 5% by weight of the tablet, such as 0.1 to about 3% by weight of the tablet.
• Usable flavors include almond, almond amaretto, apple, Bavarian cream, black cherry, black sesame seed, blueberry, brown sugar, bubblegum, butterscotch, cappuccino, caramel, caramel cappuccino, cheesecake (graham crust), chili, cinnamon redhots, cotton candy, circus cotton candy, clove, coconut, coffee, clear coffee, double chocolate, energy cow, ginger, glutamate, graham cracker, grape juice, green apple, Hawaiian punch, honey, Jamaican rum, Kentucky bourbon, kiwi, koolada, lemon, lemon lime, tobacco, maple syrup, maraschino cherry, marshmallow, menthol, milk chocolate, mocha, Mountain Dew, peanut butter, pecan, peppermint, raspberry, banana, ripe banana, root beer, RY 4, spearmint, strawberry, sweet cream, sweet tarts, sweetener, toasted almond, tobacco, tobacco blend, vanilla bean ice cream, vanilla cupcake, vanilla swirl, vanillin, waffle, Belgian waffle, watermelon, whipped cream
• the term “approximately” or “about” in reference to a number are generally taken to include numbers that fall within a range of 5%, 10%, 15%, or 20% in either direction (greater than or less than) of the number unless otherwise stated or otherwise evident from the context (except where such number would be less than 0% or exceed 100% of a possible value).
• oral chewable tablet is considered a tablet for oral use.
• the oral tablet is considered as formed by tableting, i.e., compression of a particle composition, comprising a population of particles.
• the tablet is considered a compressed tablet formed by a plurality of particles.
• the oral chewable tablet may also be referred to as a tablet or oral tablet.
• particle size relates to the ability of the particles to move through or be retained by sieve holes of a specific size.
• particle size refers to the average particle size as determined according to European Pharmacopoeia 9.1 when using test method 2.9.38 particle size distribution estimation by analytical sieving, unless otherwise specifically is mentioned.
• particle or similar wording is intended to denote a single, discrete composition of solid matter, such as a granule or individual elements in powder, having a certain size that may deviate considerable.
• weight of the oral tablet or similar wording meaning the same is defined in the present context as weight of the oral tablet, not including the weight of an outer coating, such as a hard coating, soft coating, and the like.
• texture is meant a qualitative measure of the properties of the oral tablet and of the overall mouth-feel experienced by the user during use.
• the term “texture” encompasses measurable quantities such as hardness as well as more subjective parameters related to the feel experienced by a user.
• release in the present context is intended to mean under “in vitro” conditions if not stated otherwise.
• release rate during a certain period of time is intended to mean the amount in percentage of active ingredients that is released during the period.
• release refers to the released substance being liberated from the water-soluble matrix.
• the process of releasing a substance corresponds to the substance being dissolved in saliva.
• sustained release or “extended release” is herein intended to mean prolonged release over time.
• rapid release or “quick release” or “high release” is herein intended to mean a higher content released for a given period of time.
• controlled release is intended to mean a release of a substance from an oral tablet by the aid of active use of the oral tablet in the oral cavity of the subject, whereby the active use is controlling the amount of substance released.
• the term “turn into liquid” is intended to mean that the tablet disintegrates and the fragments or particles of the tablet are either suspended or dissolved in saliva, perceived as liquid by a test person.
• disintegrate refers to a reduction of an object to components, fragments or particles. Disintegration time may be measured in vitro or in vivo. Unless otherwise stated, the in vitro measurements are carried out in accordance to European Pharmacopeia 9.0, section 2.9.1, Disintegration of tablets and capsules.
• dissolve is the process where a solid substance enters a solvent (oral saliva) to yield a solution. Unless otherwise stated, dissolving implies a full dissolving of the compound in question.
• Disintegrant refers to an ingredient facilitating disintegration of an FDT-module, when the FDT-module comes into contact with saliva.
• Disintegrants usable within the scope of the invention may include starch, pregelatinated starch, modified starch (including potato starch, maize starch, starch 1500, sodium starch glycolate and starch derivatives), cellulose, microcrystalline cellulose, alginates, , and superdisintegrants, such as crosslinked cellulose (such as sodium carboxy methyl cellulose), crosslinked polyvinyl pyrrolidone (PVP), crosslinked starch, crosslinked alginic acid, natural superdisintegrants, and calcium silicate.
• PVP polyvinyl pyrrolidone
• Disintegrants may often be considered as measure promoting the break-up of the module into smaller fragments upon administration to facilitate nicotine release and eventual absorption.
• Crospovidone may comprise various grades, such as Kollidon CL-F or Kollidon CL-SF available from BASF.
• induced saliva generation it is noted that this induced saliva generation exceeds any saliva generation without the use of the tablet of the invention, or with a content of less than 50% dextrose.
• the induced saliva generation exceeds saliva generation when using conventional tablets without dextrose or with less than 50% dextrose.
• induced saliva generation is increased over any saliva generation associated with conventional products, e.g. by comparing with a tablet without dextrose or with less than 50% dextrose.
• the saliva generation may be tested using the following method:
• Test subject abstain from eating and drinking at least 30 minutes before initiation of any test. Immediately before introducing of the tablet into the oral cavity, the test subject swallows. The test subject refrains from swallowing during the test. Immediately after introducing of the tablet into the oral cavity, the test subject starts masticating the tablet at a frequency of 1 chew per second for 20 seconds. Then, saliva and any remains of the tablet is kept in the mouth within chewing for 10 second. 30 seconds after starting the test, the test subject discards saliva including any tablet fragments into a plastic cup, which is weighted.
• active ingredient refers to a substance that is biologically active and has a physiological effect on the human body for the benefit of the human body or part thereof. Active ingredients include active pharmaceutical ingredients, but also other active substances such as nutraceuticals or immune supporting active ingredients. In the following raw materials will refer to the mixed particles to be compressed into a tablet according to embodiments of the invention unless otherwise stated.
• the process of manufacture of the inventive tablet may be performed in a single tablet press, such as a rotary tablet press. But it may be a benefit under some circumstances to apply a separate tablet press.
• the upper punch is convex which gives the upper face of the pressed tablet a concave form.
• the shape of the punches may vary depending on the desired tablet shape.
• pressing of the tablets are performed at a force of 10 to 50 kN. In some embodiments of the invention, pressing of the tablets are performed at a force of 10 to 40 kN. In some embodiments of the invention, pressing of the tablets are performed at a force of 10 to 30 kN.
• the oral tablet according to the invention is manufactured by applying pressure to a content of particles by suitable compression means.
• the particles or powder is then pressed into a compact coherent tablet.
• the particles may for example comprise so- called primary particles or aggregated primary particles. When these are pressed, bonds are established between the particles or granules, thereby conferring a certain mechanical strength to the pressed tablet.
• powder, primary particles and aggregated primary particles may be somewhat misleading in the sense that the difference between primary particles and aggregated primary particles may very often be looked upon differently depending on the background of the user.
• aggregated primary particles refer to macro-particles comprising more or less preprocessed primary particles.
• one-layered or multi-layered tablets such as two-layered tablets or three-layered tablets.
• the tableted oral tablet according to the invention may comprise about 0.1 to about 75% by weight of an outer coating applied onto the oral tablet centre.
• suitable coating types include hard coatings, film coatings and soft coatings of any composition including those currently used in coating of tableted oral tablet.
• One presently preferred outer coating type is a hard coating, which term is used in the conventional meaning of that term including sugar coatings and sugar-free (or sugarless) coatings and combinations thereof.
• the object of hard coating is to obtain a sweet, crunchy layer, which is appreciated by the consumer and it may moreover protect the oral tablet centres for various reasons.
• the oral tablet centres are successively treated in suitable coating equipment with aqueous solutions of crystallisable sugar such as sucrose or dextrose, which, depending on the stage of coating reached, may contain other functional ingredients, e.g. fillers, binding agents, colours, etc.
• the sugar coating may contain further functional or active compounds including flavour compounds and/or active compounds.
• a suspension containing crystallisable sugar and/or polyol is applied onto the oral tablet centres and the water it contains is evaporated off by blowing with air. This cycle must be repeated several times, typically 3 to 80 times, in order to reach the swelling required.
• swelling refers to the increase in weight or thickness of the products, as considered at the end of the coating operation by comparison with the beginning, and in relation to the final weight or thickness of the coated products.
• the coating layer constitutes about 0.1 to about 75% by weight of the finished oral tablet element, such as about 10 to about 60% by weight, including about 15 to about 50% by weight.
• the outer coating of the oral tablet element of the invention is an element that is subjected to a film coating process and which therefore comprises one or more film-forming polymeric agents and optionally one or more auxiliary compounds, e.g. plasticizers, pigments and opacifiers.
• a film coating is a thin polymer-based coating applied to an oral tablet centre of any of the above forms. The thickness of such a coating is usually between 20 and 100 pm.
• the film coating is obtained by passing the oral tablet centres through a spray zone with atomized droplets of the coating materials in a suitable aqueous or organic solvent vehicle, after which the material adhering to the oral tablet centres is dried before the next portion of coating is received. This cycle is repeated until the coating is complete.
• the tablet according to the invention comprises a pharmaceutically, cosmetically or biologically active substance.
• active substances include drugs, dietary supplements, antiseptic agents, pH adjusting agents, anti-smoking agents.
• useful active substances in the form of antiseptics include salts and derivatives of guanidine and biguanidine the following types of substances with limited water-solubility: quaternary ammonium compounds (e.g. ceramine, chloroxylenol, crystal violet, chloramine), aldehydes (e.g.
• paraformaldehyde derivatives of dequaline, polynoxyline, phenols (e.g. thymol, p-chlorophenol, cresol), hexachlorophene, salicylic anilide compounds, triclosan, halogenes (iodine, iodophores, chloroamine, dichlorocyanuric acid salts), alcohols (3,4 di chlorobenzyl alcohol, benzyl alcohol, phenoxyethanol, phenylethanol), cf.
• phenols e.g. thymol, p-chlorophenol, cresol
• hexachlorophene salicylic anilide compounds
• triclosan e.g. halogenes (iodine, iodophores, chloroamine, dichlorocyanuric acid salts)
• alcohols (3,4 di chlorobenzyl alcohol, benzyl alcohol, phenoxyethanol, phenylethanol), cf.
• metal salts, complexes and compounds with limited watersolubility such as aluminum salts, (for instance aluminum potassium sulphate A1K(SO4)2, 12H2O) and salts, complexes and compounds of boron, barium, strontium, iron, calcium, zinc, (zinc acetate, zinc chloride, zinc gluconate), copper (copper chloride, copper sulphate), lead, silver, magnesium, sodium, potassium, lithium, molybdenum, vanadium should be included.
• aluminum salts for instance aluminum potassium sulphate A1K(SO4)2, 12H2O
• active substances in the form of agents adjusting the pH in the oral cavity include: acids, such as adipic acid, succinic acid, fumaric acid, or salts thereof or salts of citric acid, tartaric acid, malic acid, acetic acid, lactic acid, phosphoric acid and glutaric acid and acceptable bases, such as carbonates, hydrogen carbonates, phosphates, sulphates or oxides of sodium, potassium, ammonium, magnesium or calcium, especially magnesium and calcium.
• acids such as adipic acid, succinic acid, fumaric acid, or salts thereof or salts of citric acid, tartaric acid, malic acid, acetic acid, lactic acid, phosphoric acid and glutaric acid and acceptable bases, such as carbonates, hydrogen carbonates, phosphates, sulphates or oxides of sodium, potassium, ammonium, magnesium or calcium, especially magnesium and calcium.
• Active ingredients may comprise the below mentioned compounds or derivates thereof but are not limited thereto: Acetaminophen, Acetylsalicylic acid, Buprenorphine, Bromhexin, Celcoxib, Codeine, Diphenhydramin, Diclofenac, Etoricoxib, Ibuprofen, Indometacin, Ketoprofen, Lumiracoxib, Morphine, Naproxen, Oxycodon, Parecoxib, Piroxicam, Pseudoefedrin, Rofecoxib, Tenoxicam, Tramadol, Valdecoxib, Calciumcarbonat, Magaldrate, Disulfiram, Bupropion, Nicotine, Azithromycin, Clarithromycin, Clotrimazole, Erythromycin, Tetracycline, Granisetron, Ondansetrone, Prometazin, Tropisetron, Brompheniramine, Ceterizin, leco-Ceterizin, Chlorcyclizine, Chlor
• the invention is suitable for increased or accelerated release of active agents selected among the group of dietary supplements, , antiseptic agents, pH adjusting agents, anti-smoking agents, sweeteners, flavorings, aroma agents or drugs. Some of those will be described below.
• the active agents to be used in connection with the present invention may be any substance desired to be released from the tablet.
• the active agents, for which a controlled and/or accelerated rate of release is desired are primarily substances with a limited water-solubility, typically below 10 g/100 mL inclusive of substances which are totally water-insoluble. Examples are medicines, dietary supplements, oral compositions, anti-smoking agents, highly potent sweeteners, pH adjusting agents, flavorings etc.
• active ingredients are, for instance, paracetamol, benzocaine, cinnarizine, menthol, carvone, caffeine, cyclizine hydrochloride, 1,8-cineol, nandrolone, miconazole, mystatine, , nicotine, , other quaternary ammonium compounds, vitamin E, vitamin A, vitamin D, glibenclamide or derivatives thereof, progesterone, acetylsalicylic acid, dimenhydrinate, cyclizine, metronidazole, sodium hydrogen carbonate, the active components from ginkgo, the active components from propolis, the active components from ginseng, methadone, oil of peppermint, salicylamide, hydrocortisone or astemizole.
• active agents in the form of dietary supplements are for instance salts and compounds having the nutritive effect of vitamin B2 (riboflavin), B12, folinic acid, folic acid, niacine, biotine, poorly soluble glycerophosphates, amino acids, the vitamins A, D, E and K, minerals in the form of salts, complexes and compounds containing calcium, phosphorus, magnesium, iron, zinc, copper, iodine, manganese, chromium, selenium, molybdenum, potassium, sodium or cobalt.
• vitamin B2 riboflavin
• B12 riboflavin
• folinic acid folinic acid
• folic acid niacine
• biotine poorly soluble glycerophosphates
• amino acids amino acids
• the vitamins A, D, E and K minerals in the form of salts, complexes and compounds containing calcium, phosphorus, magnesium, iron, zinc, copper, iodine, manganese, chro
• active agents in the form of antiseptics are for instance salts and compounds of guanidine and biguanidine and the following types of substances with limited water-solubility: quaternary ammonium compounds (for instance ceramine, chloroxylenol, crystal violet, chloramine), aldehydes (for instance paraformaldehyde), compounds of dequaline, polynoxyline, phenols (for instance thymol, para chlorophenol, cresol) hexachlorophene, salicylic anilide compounds, triclosan, halogenes (iodine, iodophores, chloroamine, dichlorocyanuric acid salts), alcohols (3,4 di chlorobenzyl alcohol, benzyl alcohol, phenoxyethanol, phenylethanol), cf.
• quaternary ammonium compounds for instance ceramine, chloroxylenol, crystal violet, chloramine
• aldehydes for instance paraformaldehyde
• metal salts, complexes and compounds with limited water-solubility such as aluminum salts, (for instance aluminum potassium sulphate A1K(SO4)2,12H2O) and furthermore salts, complexes and compounds of boron, barium, strontium, iron, calcium, zinc, (zinc acetate, zinc chloride, zinc gluconate), copper (copper chloride, copper sulfate), lead, silver, magnesium, sodium, potassium, lithium, molybdenum, vanadium should be included.
• aluminum salts for instance aluminum potassium sulphate A1K(SO4)2,12H2O
• active agents in the form of agents adjusting the pH in the oral cavity include for instance: acceptable acids, such as adipic acid, succinic acid, fumaric acid, or salts thereof or salts of citric acid, tartaric acid, malic acid, acetic acid, lactic acid, phosphoric acid and glutaric acid and acceptable bases, such as carbonates, hydrogen carbonates, phosphates, sulfates or oxides of sodium, potassium, ammonium, magnesium or calcium, especially magnesium and calcium.
• acceptable acids such as adipic acid, succinic acid, fumaric acid, or salts thereof or salts of citric acid, tartaric acid, malic acid, acetic acid, lactic acid, phosphoric acid and glutaric acid
• acceptable bases such as carbonates, hydrogen carbonates, phosphates, sulfates or oxides of sodium, potassium, ammonium, magnesium or calcium, especially magnesium and calcium.
• active agents in the form of anti-smoking agents include for instance: nicotine, tobacco powder or silver salts, for instance silver acetate, silver carbonate and silver nitrate.
• active agents are medicines of any type.
• active agents in the form of medicines include caffeine, salicylic acid, salicyl amide and related substances (acetylsalicylic acid, choline salicylate, magnesium salicylate, sodium salicylate), paracetamol, salts of pentazocine (pentazocine hydrochloride and pentazocinelactate), buprenorphine hydrochloride, codeine hydrochloride and codeine phosphate, morphine and morphine salts (hydrochloride, sulfate, tartrate), methadone hydrochloride, ketobemidone and salts of ketobemidone (hydrochloride), beta-blockers, (propranolol), calcium antagonists, verapamil hydrochloride, nifedinpine as well as suitable substances and salts thereof mentioned in Pharm.
• active ingredients include vitamins.
• Vitamins include A, Bl, B2, B6, B12, Folinic acid, Folic acid, niacin, Pantothenic acid, biotine, C, D, E, K.
• Minerals include Calcium, phosphor, magnesium, iron, Zinc, Copper, lod, Mangan, Crom, Selene, Molybden.
• Other active ingredients include: Q10®, enzymes. Natural drugs including Ginkgo Biloba, ginger, and fish oil.
• active ingredients include migraine drugs such as Serotonin antagonists: Sumatriptan, Zolmitriptan, Naratriptan, Rizatriptan, Eletriptan; nausea drugs such as Cyclizin, Cinnarizin, Dimenhydramin, Difenhydrinat; hay fever drugs such as Cetrizin, Loratidin, pain relief drugs such as Buprenorfin, Tramadol, oral disease drugs such as Miconazol, Amphotericin B, Triamcinolonaceton; and the drugs Cisaprid, Domperidon, Metocl oprami d.
• the invention relates to the release of Nicotine and its salts.
• the active ingredient is selected from active ingredients for the throat selected from acetylcysteine, ambroxol, amylmetacresol, benzocaine, bisacodyl, bismuth subsalicylate, bromhexine, cetirizine, dextromethorphan hydrobromide, 2,4-dichlorobenzyl alcohol, doxylamine succinate, eucalyptus oil, flurbiprofen, glycerin, hexylresorcinol, lidocaine, menthol, myrrh, paracetamol, pectin, peppermint oil, phenol, phenylephrine, povidone-iodine, pseudoephedrine, ranitidine, simethicone, sodium docusate, spearmint, zinc, or any combination thereof; active ingredients for the gastrointestinal tract selected from alginate, atenolol, aspirin (acetylsalicylicaminophen,
• the “tablet” is intended to mean a “fast disintegrating tablet” (“FDT”), or similar wording, such as “orally disintegrating tablet” (“ODT”).
• FDT fast disintegrating tablet
• ODT electronically disintegrating tablet
• the tablet according to the invention is made as one module, contrary to two or more modules, then the tablet is intended to be an FDT tablet.
• the tablet is made of more than one module, such as two modules, such additional module is intended to be a “lozenge” module or “chewing gum module”, which provides a longer disintegration time compared to the FDT module according to the invention.
• the combination of an “FDT” module and a “lozenge” module contributes to another aspect of the invention.
• a “lozenge” module or “chewing gum module” may also comprise elements from the “FDT” modules but is generally different in composition, providing an extended disintegration time.
• module is generally intended to be composed of a composition of matter with substantially the same characteristics throughout the module. Hence, if two module are present, then the two modules are different in composition and generally have two different characteristics throughout each module. In the present context, if only one module is present, then this module is considered an FDT tablet. On the other hand, if two modules are present, then the tablet is composed of an FDT tablet or FDT tablet module fused with a lozenge tablet or lozenge module.
• the term “fused” is intended to mean that the tablet is gathered together by means of compression force.
• the lozenge module is made as the first module and the FDT module is made as the second module.
• the tablet may be composed of more than two module.
• the lozenge module may in certain embodiments be replaced by a gum base module.
• the invention provides an attractive bi-phasic delivery of masking, even if the delivery of nicotine is “single-phased”.
• dextrose was added to a mixing container. Active ingredients, flavors, high-intensity sweeteners, and optional other components were added to the container. The mixture was sieved and tumbled in a FUCHS Mixomat-A at approximately 25 rpm for 4 minutes. A processing aid was added and the mixture was tumbled at approximately 25 rpm for another 1 minute. Hereafter, the mixture was ready for tableting.
• the mixture was subsequently led to a standard tablet pressing machine (3090i, available from Fette GmbH) comprising dosing apparatus (P 3200 C, available from Fette GmbH, Germany) and pressed into two-layered tablets.
• a Riva Picoola Bi-layer DC-PL -015 was used.
• the tablets were pressed using a pre- compression force of about 2.2 kN to form a first layer. After pre-compression of the first layer another portion of powder was added in the apparatus and a compression force of 10-30 kN was applied, unless otherwise indicated. There were 11 punches on the rotor, and the rotor speed used was 5 rpm.
• the individual tablets had a weight of approx. 1500 mg where the layers constituted weight ratios of about 1 : 1, unless otherwise stated in the examples below. Punch used: 15.00 mm, circular, shallow concave, B tooling.
• Dextrose applied according to the examples was C*dexTM 02001 commercially available from Cargill, or C*dexTM 02030 provided by Cargill, or C*dexTM 02032 provided by Cargill, or Cerelose® dextrose 020010 provided by Ingredion, or Royal- T® provided by Ingredion.
• separate binders applied were applied, such as HPC and HPMC. HPC was available as Klucel Nutra D from Ashland.
• HPMC was available as Methocel 4KM from Dow. When microcrystalline cellulose was applied as a comparative binder, it was Avicel PH-102 commercially available from Dupont. When maltodextrin was applied as a binder, it was C*dryTM MD from Cargill.
• composition of two-layered dextrose tablets in presence of an active ingredient in different amounts Composition of two-layered dextrose tablets in presence of an active ingredient in different amounts
• Dextrose tablets based on the procedure in Example 1 were made with the formulations outlined in the examples below. In all of the tablet examples, the amount of the various ingredients is given as % by weight of each layer of the tablet.
• the same components were applied in the different layers of the tablet except for the flavor type which may be varied in different layers. Color in minute amounts was optionally added to one or more layers. The layers had the same weight percentages by weight of the tablet.
• Dextrose was C*dexTM 02032 commercially available from Cargill. **The active ingredient was vitamin C available from DSM .
• the first layer of the tablets was pre-compressed with a force of about 2,2 kN and the second layer was compressed with a force of about 20 kN.
• Tablets 100 - 104 were repeated as tablets 100A - 104A using C*dexTM 02030 available from Cargill and as tablets 100B - 104B using Royal-T® available from Ingredion.
• composition of two-layered dextrose tablets with different grades of dextrose in each layer is composition of two-layered dextrose tablets with different grades of dextrose in each layer
• Dextrose tablets based on the procedure in Example 1 were made with the formulations outlined in the examples below. In all of the tablet examples, the amount of the various ingredients is given as % by weight of each layer of the tablet.
• the same components were applied in the different layers of the tablet except for the flavor type which may be varied in different layers. Color in minute amounts was optionally added to one or more layers. The layers had the same weight percentages by weight of the tablet.
• composition of two-layered dextrose tablets with different grades of dextrose in each layer is composition of two-layered dextrose tablets with different grades of dextrose in each layer
• Dextrose tablets based on the procedure in Example 1 were made with the formulations outlined in the examples below. In all of the tablet examples, the amount of the various ingredients is given as % by weight of each layer of the tablet.
• the same components were applied in the different layers of the tablet except for the flavor type which may be varied in different layers. Color in minute amounts was optionally added to one or more layers. The layers had the same weight percentages by weight of the tablet.
• composition of two-layered dextrose tablets with different grades of dextrose in each layer is composition of two-layered dextrose tablets with different grades of dextrose in each layer
• Dextrose tablets based on the procedure in Example 1 were made with the formulations outlined in the examples below. In all of the tablet examples, the amount of the various ingredients is given as % by weight of each layer of the tablet.
• the same components were applied in the different layers of the tablet except for the flavor type which may be varied in different layers. Color in minute amounts was optionally added to one or more layers. The layers had the same weight percentages by weight of the tablet.
• Table 4 *Dextrose in layer 1 was C*dexTM 02001 commercially available from Cargill and dextrose in layer 2 was Royal-T® provided by Ingredion. **The active ingredient was melatonin available from JiaHerb. The first layer of the tablets was pre-compressed with a force of about 2,2 kN and the second layer was compressed with a force of about 20 kN. ***The binder was HPC. No binder was added to layer 2, hence Royal-T® was added in an amount of 95.9% in layer two of all tablets.
• Dextrose tablets based on the procedure in Example 1 were made with the formulations outlined in the examples below.
• the amount of the various ingredients is given as % by weight of each layer of the tablet.
• the same components were applied in the different layers of the tablet except for the flavor type which may be varied in different layers.
• Color in minute amounts was optionally added to one or more layers.
• the layers had the same weight percentages by weight of the tablet.
• Table 5 *Dextrose in layer 1 and 2 was C*dexTM 02001 commercially available from Cargill. **The active ingredient was melatonin available from JiaHerb. The first layer of the tablets was precompressed with a force of about 2,2 kN and the second layer was compressed with a force of about 20 kN.
• Tablets 140 - 144 were repeated as tablets 140A - 144A using Cerelose® dextrose 020010 available from Ingredi on.
• composition of two-layered dextrose tablets with different actives in each layer Composition of two-layered dextrose tablets with different actives in each layer
• Dextrose tablets based on the procedure in Example 1 were made with the formulations outlined in the examples below. In all of the tablet examples, the amount of the various ingredients is given as % by weight of each layer of the tablet.
• the same components were applied in the different layers of the tablet except for the flavor type which may be varied in different layers. Color in minute amounts was optionally added to one or more layers. The layers had the same weight percentages by weight of the tablet.
• composition of two-layered dextrose tablets with different actives in each layer Composition of two-layered dextrose tablets with different actives in each layer
• Dextrose tablets based on the procedure in Example 1 were made with the formulations outlined in the examples below.
• the amount of the various ingredients is given as % by weight of each layer of the tablet.
• the same components were applied in the different layers of the tablet except for the flavor type which may be varied in different layers.
• Color in minute amounts was optionally added to one or more layers.
• the layers had the same weight percentages by weight of the tablet.
• composition of two-layered dextrose tablets in presence of an active ingredient in different amounts Composition of two-layered dextrose tablets in presence of an active ingredient in different amounts
• Dextrose tablets based on the procedure in Example 1 were made with the formulations outlined in the examples below. In all of the tablet examples, the amount of the various ingredients is given as % by weight of each layer of the tablet.
• the same components were applied in the different layers of the tablet except for the flavor type which may be varied in different layers. Color in minute amounts was optionally added to one or more layers. The layers had the same weight percentages by weight of the tablet.
• Dextrose was C*dexTM 02032 commercially available from Cargill. **The active ingredient was calcium carbonate available from Nutrigranulation.
• the first layer of the tablets was precompressed with a force of about 2,2 kN and the second layer was compressed with a force of about 20 kN.
• Tablets 170 - 174 were repeated as tablets 170A - 174A using C*dexTM 02030 available from Cargill and as tablets 170B - 174B using Royal-T® available from Ingredion.
• Example 10 Tablets 170 - 174 were repeated as tablets 170A - 174A using C*dexTM 02030 available from Cargill and as tablets 170B - 174B using Royal-T® available from Ingredion. Example 10
• breaking point test For each version of the tablets, a breaking point test, a friability test and a dissolution time measurement were performed.
• a PTB 311 from Pharma Test was used for measuring breaking point.
• the friability test was made in accordance to European Pharmacopoeia 9.1, test method 2.9.7. by using a pharmaceutical friability-tester PTF 10E from Pharma Test.
• the following method was used. 15 mL of 0.02 M potassium dihydrogen phosphate-buffer (pH adjusted to 7.4) is added to 50 mL of water in a measuring tube with a screw cap. The tablet is inserted in the measuring tube and the screw cap is fastened. The measuring tube is fixated horizontally. The measuring tube is vibrated at about 110 RPM such that the tablet can move back and forth in the measuring tube. The measuring tube is vibrated until the tablet or module thereof in question is completely dissolved and the time of vibration is noted as the dissolution time.
• test set-up was composed of 8 test persons in a test panel. All of the test persons were healthy individuals appointed on an objective basis according to specified requirements. The sensory analysis was performed according to ISO 4121-2003 in testing conditions following ISO 8589. The result is an average of the results of the 8 individuals.
• test persons gave a rating from “+” to where “+” is poor and “+++++” is excellent.“0“ indicated that it was not tested.
• Six different parameters were tested in a test panel:
• “Liquid feeling” the impression of the tablet when placed in the mouth and chewed with respect to the sense of liquid in the mouth. For instance, if more liquid is sensed during and/or after chewing, then the score is high.
• “Mouthfeel” the overall impression of the tablet during chewing with respect to mouthfeel, including melting and tacking sensations.
• a high scoring mouthfeel is associated with a clean liquid (no sense of particles), no tablet residuals sticking in teeth and a creamy feeling (higher viscosity than water).
• a low scoring mouthfeel is associated with sense of particles in the liquid (incomplete dissolution), tablet residuals sticking in the teeth and a watery feeling of the liquid.
• Example 12 Results of two-layered dextrose tablets in presence of an active ingredient in different amounts
• the results reveal that the content of actives was suitable in the range from 0.1 to 40% by weight of the active ingredient when compressed in a two-layered tablet according to the invention. It was a surprise that a high content of active ingredients was suitable in the two-layered configuration.
• results of two-layered dextrose tablets with different grades of dextrose in each layer Table 10: Tested in compliance with Examples 10 and 11. Generally, the results reveal that the content of actives was suitable in the range from 0.1 to 40% by weight of the active ingredient when compressed in a two-layered tablet according to the invention. It was a surprise that a high content of active ingredients was suitable in the two-layered configuration.
• the results reveal that the content of actives was suitable in the range from 0.1 to 40% by weight of the active ingredient when compressed in a two-layered tablet according to the invention. Additionally, the results reveal that the two different grades in the different layers of the tablets were suitable according to the invention.
• the results reveal that adding a separate binder in layer 1 was suitable to obtain a good result when compressed in a two-layered tablet according to the invention.
• Table 15 Tested in compliance with Examples 10 and 11. Generally, the results reveal that the content of actives was suitable in the range from 0.1 to 40% by weight of the active ingredient when compressed in a two-layered tablet according to the invention.
• the results reveal that the content of actives was suitable in the range from 0.1 to 40% by weight of the active ingredient when compressed in a two-layered tablet according to the invention.
• Dextrose tablets based on the procedure in Example 1 were made with the formulations outlined in the examples below, here including caffeine in an amount of 100 mg and optionally vitamin B premix in an amount of 15 mg as active ingredient.
• the amount of the various ingredients is given as % by weight of each layer of the tablet. Unless specifically indicated, the same components were applied in the different layers of the tablet except for the flavor type which may be varied in different layers. Color in minute amounts was optionally added to one or more layers. The layers had the same weight percentages by weight of the tablet.
• Dextrose tablets based on the procedure in Example 1 were made with the formulations outlined in the examples below, here including ginseng in an amount of 10 mg and optionally vitamin B premix in an amount of 10 mg as active ingredient.
• the amount of the various ingredients is given as % by weight of each layer of the tablet. For all samples in this example, the total tablet weight is 1000 mg.
• the same components were applied in the different layers of the tablet except for the flavor type which may be varied in different layers. Color in minute amounts was optionally added to one or more layers. The layers had the same weight percentages by weight of the tablet.
• Dextrose tablets based on the procedure in Example 1 were made with the formulations outlined in the examples below, here including L-theanine in an amount of 100 mg and optionally caffeine in an amount of 50 mg as active ingredient.
• the amount of the various ingredients is given as % by weight of each layer of the tablet.
• the same components were applied in the different layers of the tablet except for the flavor type which may be varied in different layers. Color in minute amounts was optionally added to one or more layers. The layers had the same weight percentages by weight of the tablet.
• Dextrose tablets based on the procedure in Example 1 were made with the formulations outlined in the examples below, here including vitamin C in an amount of 500 mg or a herbal blend with vitamin C and other vitamins/minerals in an amount of 450 mg as active ingredient.
• the amount of the various ingredients is given as % by weight of each layer of the tablet. Unless specifically indicated, the same components were applied in the different layers of the tablet except for the flavor type which may be varied in different layers. Color in minute amounts was optionally added to one or more layers. The layers had the same weight percentages by weight of the tablet.
• Dextrose tablets based on the procedure in Example 1 were made with the formulations outlined in the examples below, here including active ingredients suitable for treating cough and cold symptoms.
• the amount of the various ingredients is given as % by weight of each layer of the tablet.
• the same components were applied in the different layers of the tablet except for the flavor type which may be varied in different layers. Color in minute amounts was optionally added to one or more layers. The layers had the same weight percentages by weight of the tablet. For all samples in this example, the total tablet weight is 1750 mg.
• dextrose tablet 211 was providing a superior mouthfeel and liquifying sensation compared to the commercially available product Airborne which contains the same type of actives as dextrose tablet 211.
• the two-layered tablets according to the invention were compared to one-layered compressed tablets that were made by the same tools and conditions as outlined in Example 1. All tablets were prepared and made according to Example 1 but the one layered tablets were only made by adding one portion of tablet material and applying one varying main compression force to the tablets (without a pre-compression force), whereas the two-layered tablets were made by applying a pre-compression force of about 2.2 kN on a first portion of material to form a first layer for all tablets and a varying main compression force applied after adding a second portion of material to form the final two-layered tablets.
• Table 23 *one-layered tablets. **two-layered tablets. Dextrose was C*dexTM 02001 or C*dex TM 02032 commercially available from Cargill or Royal- ® commercially available from Ingredion.
• friability for one-layered tablets was on a lower level with respect to the dextrose grades C*dex 02032 and Royal-T compared to the grade C*dex 02001. Also, a low friability level was already obtained by a compression force of about 20 kN for all tablets.
• Table 25 *Dextrose w 2001 or C*dexTM 02032 commercially available from Cargill or Royal-T® commercially available from Ingredion.
• Example 30 Tablet hardness of two-layered tablets of Example 26

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